Progressive supranuclear palsy (PSP) is a sporadic tauopathy with unknown cause. The H1 tau haplotype is implicated in its etiology;however, it is also present in 60% of normal controls. This, coupled with late symptom onset, indicates that genetics alone does not cause PSP. Support for the environmental factor hypothesis stems from animal models and the observed association between PSP and exposure to mitochondrial complex I inhibitors (i.e., acetogenins), which are neurotoxic to dopaminergic neurons. Impaired metabolism in PSP mitochondria and oxidative injury in affected brain areas also support this hypothesis. Hence, genes and environment may both play a role either alone or through their interactions. This application will determine: 1) if there is an association between PSP and the HI/HI genotype, specific HI sub-haplotypes, alpha-synuclein polymorphisms or parkin gene deficits, or if there are gene-gene interactions;2) if there is an association between PSP occupational and/or environmental chemical exposures functionally or structurally similar to rotenone/acetogenins;and 3) if hypertension or traumatic brain injury prior to symptom-onset is associated with PSP. To disentangle the complex etiology of PSP, this case-control multicenter study involves 500 PSP cases, 500 age/gender matched primary controls, and 500 secondary controls for genetic confirmation. Previous case-control studies have been inconclusive because of limitations in size, scope, or structure. This is the first adequately powered series of PSP cases with matched controls that has the necessary infrastructure to address our hypotheses and explore gene-environmental interactions. As a result, it will help resolve controversies concerning the cause(s) of PSP and will stimulate new avenues of pathogenesis research and prophylactic therapies. Understanding the etiology of PSP may also help explain the causes of other tauopathies such as Alzheimer's disease. This multidisciplinary team of movement disorder specialists, epidemiologists, geneticists, biostatisticians, industrial hygienist and toxicologist is well suited to unravel the complex etiology of PSP. The use of the NINDS cell repository for genetic banking will also allow DNA sample sharing with other investigators.